Colbert kicked things off by highlighting one of Louis-Dreyfus' lesser-known roles.

"We're going to be hearing a lot tonight about her characters like Elaine (from "Seinfeld") and Old Christine (from "The New Adventures of Old Christine") but I want to talk about another performance, one that truly speaks to me," the "Late Show" host said. "I bet it speaks to a lot of people in this room, too. I'm talking about Julia's turn as Jeanette Cooper in 1986's 'Troll.' "

Similarly, "The Big Sick" writer/star Kumail Nanjiani also reached back into the archives, pulling out a photo from a GQ shoot in which Louis-Dreyfus appears to be hooking up with a clown.

"I'm seeing you explain (this photo) to your mom, right now," Nanjiani assessed. "I cannot believe it has not come up before today."

Tina Fey made things personal.

"I've always liked Julia. Maybe because I'd like to believe that we have a lot in common," Fey said. "We both studied comedy in Chicago, we both lost our virginity to (Louis-Dreyfus' husband) Brad Hall." After taking a beat, Fey added: "Just me?"

Fey continued, paying homage to Louis-Dreyfus' "Seinfeld" character: "Julia made the bold choice for her character Elaine Benes to wear long, loose dresses, flat shoes and over-sized coats and a center barrette. Julia was letting us know that she was the real deal, comedy-wise, and she didn't need to give us midriff for (us) to watch her work because – here's the secret – Julia's not afraid to be unlikable – not onscreen and not in person. Just try sharing an elevator with her."

Larry David, while not there in person, took jabs at the guest of honor via video message, because he admittedly is "kind of lazy."

"I want to congratulate Julia for this unbelievably prestigious award," the "Seinfeld" co-creator said. "But I gotta say, the lengths that she went through to get it, frankly I was a little surprised ... that whole cancer thing? Cancer? Honestly, I gotta take my hat off to her. What a scam."

"She's such a great actress. She really committed to it," David continued. "She almost had me going for a second. I gotta say, she's done some incredible acting work... but nothing, nothing tops this cancer performance. I stand in awe."

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Julia Louis-Dreyfus is the newest recipient of the Mark Twain Prize for American Humor, which was bestowed to her at the Kennedy Center in Washington, D.C., on Oct. 21, 2018. Owen Sweeney, Owen Sweeney/Invision/AP

Many of Louis-Dreyfus' family members joined her, including mother Judith Bowles, far left, sister, actress Lauren Bowles, second from right, and her husband Patrick Fischler and their daughter Fia Fischler. ANDREW CABALLERO-REYNOLDS, AFP/Getty Images

"So many greats of American comedy have been honored over the years, and so far only one prize rescinded. Let's put up the sign," Colbert directed. A sign behind Colbert read: "It has been 167 days since last Un-Twaining."

"Skip this one. Skip it," Keegan-Michael Key, in costume as Mark Twain, said when he came across Cosby's name while ticking off a list of past recipients. "It's OK, he's not watching. It's not like PBS is the first choice on the moving picture box in the recreational room in the penitentiary."

Fey set her sights on the White House.

"By the way, everyone talks about all the parallels between 'Veep' and the current administration," she said. "But I think it's more like 'Seinfeld,' just a bunch of selfish (expletive) who don't give a crap about anyone but themselves."

Fey continued, praising Louis-Dreyfus while slighting the powers that be. "She's a tireless advocate for women's health and the environment," Fey said, "and a bunch of other stuff that won't exist pretty soon."

Once on the stage, Louis-Dreyfus joined in the Trump-bashing. "Unfortunately, the president of the United States couldn't make it tonight, either. Even though he lives in the neighborhood Mondays through Wednesdays."

Louis-Dreyfus poked fun at the celebs on hand as well.

"Kumail, thank you for being here," she said. "It is so inspiring that you were able to co-opt your wife's harrowing medical ordeal for an Oscar nomination."

"Tina Fey, you are a comedy genius, whom I admire of all humans," she said. "Tina was honored with the Mark Twain Prize, too. You know, before they got real serious about (it)."

But the best burn she saved for her family.

"According to Wikipedia, I have two sons, Charlie and Henry," she said. "You know when you're a working mother, you really worry about the time spent away from your kids. You try your best to be there as much as possible, but the truth is, is that you miss stuff and you worry that they're going to just get all screwed up ... and then you get the Mark Twain Prize. I gotta say, it's worth it."

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On Sept. 28, Julia Louis-Dreyfus, one of America's funniest women, caught fans by surprise with some serious news: A breast cancer diagnosis. "One in eight women get breast cancer," she wrote on Twitter. "Today, I'm the one." Click forward to see moments from her career. Melissa Lyttle, USA TODAY NETWORK

Elaine held several jobs of 'Seinfeld' but the most memorable might have been as an editor of the J. Peterman catalog. She had to talk Kramer (Michael Richards) off the ledge when he had second-thoughts about selling his life story to the catalog owner (John O'Hurley, right). J. Cohen, NBC

if you ever wanted to know what she looked like in a princess costume, now you know. In 2000, she played one in 'The Wonderful World of Disney's live-action 'Gepetto.' (From left: Rene Auberjonois, Drew Carey, Seth Adkins and Louis-Dreyfus) Bob D'Amico, ABC

In 2002, Louis-Dreyfus returned to sitcom life, playing a nightclub singer in NBC's 'Watching Ellie.' The show borrowed '24's real-time approach, but its time ran out after two seasons. Jeffrey Thurnher, NBC

In 2006, she left her longtime network home of NBC for CBS to star in 'The New Adventures of Old Christine.' She played the working mom of a young son (Trevor Gagnon) whose ex-husband (Clark Gregg) had a new girlfriend (Emily Rutherford) also named Christine. WARNER BROS.

In 2013, Louis-Dreyfus starred opposite James Gandolfini in one of his final roles, the romantic comedy 'Enough Said.' The 'Sopranos' star died on June 19, 2013, three months before the film was released. Lacey Terrell, AP

In 2017, she made Emmy history by winning outstanding lead actress in a comedy for the sixth consecutive time. She has eight acting Emmys in total, which ties with Cloris Leachman. Robert Hanashiro, USA TODAY

Over the run of 'Veep,' she's made a running joke of involving the people who play her assistants in her victory speeches. Here, Matt Walsh, who plays her communications director Mike McLintock does the honors at the 2014 Screen Actors Guild Awards. Robert Hanashiro, USA TODAY

In March 2017, Louis-Dreyfus and husband Brad Hall endeared themselves to college basketball fans by joining the cheering section for Northwestern University, where son Charlie plays ball. The team won its first-ever NCAA tournament game over Vanderbilt. David Banks, USA TODAY Sports